Percutaneous Mitral Valve Edge-to-Edge Repair

J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 6 4 , N O . 9 , 2 0 1 4

ª 2 0 1 4 B Y T H E A M E R I C A N CO L L E G E O F C A R D I O L O G Y F O U N DA T I O N I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0 0

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Percutaneous Mitral ValveEdge-to-Edge RepairIn-Hospital Results and 1-Year Follow-Up of 628 Patients ofthe 2011–2012 Pilot European Sentinel Registry

Georg Nickenig, MD, PHD,* Rodrigo Estevez-Loureiro, MD, PHD,y Olaf Franzen, MD,z Corrado Tamburino, MD, PHD,xMarc Vanderheyden, MD,k Thomas F. Lüscher, MD,{Neil Moat, MS,# Susanna Price, MD, PHD,** Gianni Dall’Ara, MD,yReidar Winter, MD, PHD,yy Roberto Corti, MD,{ Carmelo Grasso, MD,x Thomas M. Snow, MD,y Raban Jeger, MD,zzStefan Blankenberg, MD,xx Magnus Settergren, MD, PHD,yy Klaus Tiroch, MD,kk Jan Balzer, MD,{{Anna Sonia Petronio, MD,## Heinz-Joachim Büttner, MD,*** Federica Ettori, MD,yyy Horst Sievert, MD,zzzMaria Giovanna Fiorino, MD,xxx Marc Claeys, MD, PHD,kkk Gian Paolo Ussia, MD,{{{ Helmut Baumgartner, MD,###Salvatore Scandura, MD,x Farqad Alamgir, MD,**** Freidoon Keshavarzi, MD,**** Antonio Colombo, MD,yyyyFrancesco Maisano, MD, PHD,zzzz Henning Ebelt, MD,xxxx Patrizia Aruta, MD,x Edith Lubos, MD,xxBjörn Plicht, MD,kkkk Robert Schueler, MD,* Michele Pighi, MD,y Carlo Di Mario, MD, PHD,y on behalf of theTranscatheter Valve Treatment Sentinel Registry Investigators of the EURObservational Research Programme of theEuropean Society of Cardiology

ABSTRACT

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BACKGROUND The use of transcatheter mitral valve repair (TMVR) has gained widespread acceptance in Europe, but

data on immediate success, safety, and long-term echocardiographic follow-up in real-world patients are still limited.

OBJECTIVES The aim of this multinational registry is to present a real-world overview of TMVR use in Europe.

METHODS The Transcatheter Valve Treatment Sentinel Pilot Registry is a prospective, independent, consecutive

collection of individual patient data.

RESULTS A total of 628 patients (mean age 74.2 � 9.7 years, 63.1% men) underwent TMVR between January 2011 and

December 2012 in 25 centers in 8 European countries. The prevalent pathogenesis was functional mitral regurgitation

(FMR) (n ¼ 452 [72.0%]). The majority of patients (85.5%) were highly symptomatic (New York Heart Association

functional class III or higher), with a high logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation)

(20.4 � 16.7%). Acute procedural success was high (95.4%) and similar in FMR and degenerative mitral regurgitation

(p ¼ 0.662). One clip was implanted in 61.4% of patients. In-hospital mortality was low (2.9%), without significant

differences between groups. The estimated 1-year mortality was 15.3%, which was similar for FMR and degenerative

mitral regurgitation. The estimated 1-year rate of rehospitalization because of heart failure was 22.8%, significantly

higher in the FMR group (25.8% vs. 12.0%, p[log-rank] ¼ 0.009). Paired echocardiographic data from the 1-year

follow-up, available for 368 consecutive patients in 15 centers, showed a persistent reduction in the degree of mitral

regurgitation at 1 year (6.0% of patients with severe mitral regurgitation).

CONCLUSIONS This independent, contemporary registry shows that TMVR is associated with high immediate

success, low complication rates, and sustained 1-year reduction of the severity of mitral regurgitation and improvement

of clinical symptoms. (J Am Coll Cardiol 2014;64:875–84) © 2014 by the American College of Cardiology Foundation.

m the *Department of Internal Medicine and Cardiology/Pneumology, University of Bonn, Bonn, Germany; yDepartment of

rdiology, NIHR Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom; zDepartment of Cardiology,

shospitalet, Copenhagen, Denmark; xDepartment of Cardiology, Ferrarotto Hospital, Catania, Italy; kDepartment of Cardiology,

V Ziekenhuis, Aalst, Belgium; {Department of Cardiology, University Hospital of Zurich, Zurich, Switzerland; #Cardiac Surgery

partment, NIHR Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom; **Intensive Care Unit, NIHR

medical Research Unit, Royal Brompton Hospital, London, United Kingdom; yyDepartment of Cardiology, Karolinska Uni-

rsity Hospital, Stockholm, Sweden; zzDepartment of Cardiology, University Hospital Basel, Basel, Switzerland; xxDepartment of

General an

Helios Klin

Germany;

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yyyCardiothdioVasculä

kkkDepartmVergata, R

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ABBR EV I A T I ON S

AND ACRONYMS

CI = confidence interval

DMR = degenerative mitral

regurgitation

EuroSCORE = European

System for Cardiac Operative

Risk Evaluation

FMR = functional mitral

regurgitation

LVEF = left ventricular ejection

fraction

MR = mitral valve regurgitation

MV = mitral valve

NYHA = New York Heart

Association

OR = odds ratio

SPAP = systolic pulmonary

artery pressure

TMVR = transcatheter mitral

valve repair

Nickenig et al. J A C C V O L . 6 4 , N O . 9 , 2 0 1 4

Percutaneous Mitral Valve Repair S E P T E M B E R 2 , 2 0 1 4 : 8 7 5 – 8 4

876

M itral valve surgery is the treat-ment of choice for patients withsevere mitral regurgitation (MR)

who develop symptoms and/or demonstrateworsening of left ventricular (LV) function(1) (Figure 1); however, a significant numberof patients cannot undergo mitral valve(MV) surgery because of their prohibitive sur-gical risk (2). Previous reports suggest thatthis may account for approximately one-half

SEE PAGE 885

of the patients being considered for mitralsurgery (3,4). The MitraClip system (AbbottVascular, Santa Clara, California), conceivedfor transcatheter mitral valve repair (TMVR),received regulatory approval in Europe in2008 and has already gained widespread clin-ical application. The system is based on theedge-to-edge repair concept, a techniqueproposed by Alfieri to simplify surgical treat-

ment in suitable high-risk candidates. The EVEREST

d Interventional Cardiology, Universitäres Herzzentrum Hambur

ikum Wuppertal, Wuppertal, Germany; {{Department of Cardi

##Cardiac Catheterization Laboratory, Cardiothoracic and Vascu

a, Italy; ***Department of Cardiology and Angiology II, Universitä

oracic Department, Spedali Civili Brescia, Brescia, Italy; zzzDepres Centrum Frankfurt, Frankfurt, Germany; xxxDepartment of C

ent of Cardiology, University Hospital Antwerpen, Edegem, Bel

oma, Italy; ###Department of Cardiology and Angiology, U

ment of Cardiology, Castle Hill Hospital, Cottingham, United King

Raffaele, Milano, Italy; zzzzDepartment of Cardiovascular Surgery

ment of Cardiology, Universitätsklinikum Halle/Saale, Halle/Saale

Clinic Essen, Essen, Germany. Dr. Franzen has received honoraria

Vascular. Dr. Lüscher has received a research grant from Abbott.

as an educational contract with Medtronic; and serves on the med

Abbott. Dr. Settergren serves as a proctor and advisory board mem

cular. Dr. Petronio serves as a clinical proctor for Medtronic. D

has received study honoraria, travel expenses, and consulting

ium, Avinger, Bard, Boston Scientific, Bridgepoint, Carag, Cardiac

CGuard, Coherex, Contego, Covidien, CSI, CVRx, EndoCross, ev3,

InSeal Medical, Lumen Biomedical, HLT, Lifetech, Lutonix, Maya

e, pfm Medical, Recor, ResMed, Rox Medical, SentreHeart, Spectra

, Vascular Dynamics, Venus Medical, Veryan, and Vessix; he h

nd he has stock options in CardioKinetix, Access Closure, V

artner has received travel support from Abbott, St. Jude Medica

and speaker fees from Edwards Lifesciences. Dr. Maisano serves as

h Cardio; he receives royalties from Edwards Lifesciences; and he

Abbott. Dr. Plicht receives lecture honoraria and travel grants from

o relationships relevant to the contents of this paper to disclose. At

the EURObservational Research Programme: Gold—Abbott Vas

Daiichi-Sankyo Europe, Menarini International Operations, Novar

gen and Bayer Pharma. Bronze—Boston Scientific International an

servational Research Programme (EORP) department of the Europ

ere performed by Cécile Laroche with the support of Renato Urso. O

oordinator, EORP; Thierry Ferreira, Head of Department, EORP; a

as, Michel Komajda, Fausto Pinto, Angeles Alonso, David Woo

-Lundqvist, Stephan Windecker, Stefan Anker, Uwe Zeymer, Aldo

t received April 3, 2014; revised manuscript received May 13, 2014

II (Endovascular Valve Edge-to-Edge Repair Study II) -randomized trial (5) showed that TMVR was lesseffective than surgery in reducing MR but inducedfewer perioperative adverse events and yieldedsimilar improvement in functional status. These re-sults were maintained at 4 years in patients with asuccessful initial repair (6). Subsequent observationalstudies with wider clinical and echocardiographic in-clusion criteria have confirmed the benefit of TMVRin patients with severe LV dysfunction, patients notresponding to cardiac resynchronization therapy,and patients deemed inoperable or at high surgicalrisk (7–16). The majority of these studies came froma handful of high-volume centers, early in their appli-cation of the technique, and included only a smallnumber of selected patients. The TCVT (Transcath-eter Valve Treatment Sentinel Pilot Registry) is partof the European Society of Cardiology EuroObserva-tional Research Programme and reports immediateand 12-month follow-up results of 628 consecutivepatients treated between January 2011 and December2012 in 25 centers in 8 European countries. The aim of

g, Hamburg, Germany; kkDepartment of Cardiology,

ology, Universitätsklinikum Düsseldorf, Düsseldorf,

lar Department, Azienda Ospedaliero Universitaria

ts-Herzzentrum Freiburg, Bad Krozingen, Germany;

artment of Cardiology and Vascular Medicine, Car-

ardiology, Ospedale Civico ARNAS, Palermo, Italy;

gium; {{{Department of Cardiology, Policlinico Tor

niversitätsklinikum Münster, Münster, Germany;

dom; yyyyDepartment of Cardiology, Università degli

, Università degli Studi San Raffaele, Milano, Italy;

, Germany; and the kkkkDepartment of Cardiology,

and a grant from and served on the speakers’ bureau

Mr. Moat is a consultant and proctor for Medtronic.

ical advisory board for Abbott. Dr. Grasso serves as a

ber for and has received an educational grant from

r. Ettori serves as a clinical proctor for Medtronic.

fees from Abbott, Access Closure, AGA, Angiomed,

Dimensions, CardioKinetix, CardioMEMS, Cardiox,

FlowCardia, Gardia, Gore, Guided Delivery Systems,

Medical, Medtronic, NDC, Occlutech, Osprey, Ostial,

netics, SquareOne, Svelte Medical Systems, Trireme,

as received grant support from Cook and St. Jude

elocimed, Lumen Biomedical, Coherex, and SMT.

l, and Direct Flow Medical; and travel support and

a consultant for Abbott, Medtronic, St. JudeMedical,

is a cofounder of 4Tech. Dr. Lubos has received hon-

Abbott Vascular. All other authors have reported that

the time of the registry, the following companieswere

cular, Bristol-Myers Squibb, Pfizer Inc., Boehringer

tis Pharma, Sanofi-Aventis, and Servier International.

d Merck & Co., Inc. Data collection was conducted by

ean Society of Cardiology by Gerard Gracia. Statistical

verall activities were coordinated by AldoMaggioni,

nd the EORP Oversight Committee (Roberto Ferrari,

d, Nikolaos Maniadakis, Patrizio Lancellotti, Carina

Maggioni, and Luigi Tavazzi).

, accepted June 2, 2014.

J A C C V O L . 6 4 , N O . 9 , 2 0 1 4 Nickenig et al.S E P T E M B E R 2 , 2 0 1 4 : 8 7 5 – 8 4 Percutaneous Mitral Valve Repair

877

this report is to present a real-world overview of de-vice use focusing on patient characteristics, clinicalindications, techniques, in-hospital outcomes, and1-year outcomes.

FIGURE 1 Pathogenetic Process of Degenerative and Functional Mitral Regurgitation

(A) Degenerative mitral regurgitation is a consequence of a spectrum of conditions in

which morphological changes in the connective tissue of the mitral valve cause structural

lesions (such as chordal elongation, leaflet tissue expansion) that prevent normal function

of the mitral apparatus, leading to leaflet prolapse. (B) Functional mitral regurgitation is a

consequence of left ventricular remodeling after myocardial injury (dilated cardiomyo-

pathy, ischemic left ventricular insufficiency, and so on), with enlargement of the left

ventricular chamber and mitral annulus, apical and lateral migration of the papillary

muscles, leaflet tethering, and reduced closing forces. These processes lead to incomplete

coaptation of the leaflets and variable degrees of mitral regurgitation that can fluctuate

dynamically as a function of volume status, afterload, heart rhythm, and residual ischemia.

The leaflets themselves are normal, and the disease primarily affects the myocardium

rather than the valve itself. Ao ¼ ascending aorta; LA ¼ left atrium; LV ¼ left ventricle.

METHODS

Twenty-five centers in 8 European countriescontributed to this registry (Online Appendix). Theyprospectively entered data on consecutive patientsfrom January 2011 (or from the time of ethics com-mittee approval) to December 2012 via a dedicatedInternet-based Case Record Form hosted andmanaged at the European Society of Cardiology HeartHouse. The EuroObservational Research Programmeteam generated queries to clean the database andvalidate entries. A total of 155 of 628 cases (24.6%)were audited on site. This pilot registry received nodirect commercial sponsorship from the devicemanufacturer, which produced the only CE-markedcommercially available device for transcatheter MVrepair during the study period.

At participating centers, all consecutive patientsreceiving transcatheter mitral edge-to-edge repairwith TMVR were prospectively entered into the regis-try. The only exclusion criterion was refusal to signthe agreement to enter data, which was approved bythe ethics committees of the participating centers.

The MitraClip system is a 4-mm-wide, polyester-covered, cobalt-chromium, V-shaped device with2 movable arms. With the patient under generalanesthesia and with the use of fluoroscopic andtransesophageal echocardiographic guidance (17),transseptal puncture is performed, which enables theadvancement of a 24-F torqueable sheath from thefemoral vein into the left atrium. The MitraClipcatheter is then advanced across the MV into the LVwith the clip arms opened with a perpendicularorientation to the coaptation line. When the openedarms are withdrawn, the leaflets fall into the clip andare secured between the arms and the grippers,which creates a double-orifice valve. If an acceptablereduction in MR is achieved without a criticalincrease in transmitral gradient and adequate sta-bility is demonstrated, the clip is detached from thedelivery system. In patients with broad regurgitantjets, the use of a second clip is now considered acommon technique to improve results (18).

ENDPOINTS AND DEFINITIONS. Procedural successwas defined as a reduction in the degree of MRto equal to or less than moderate (#2þ) withoutcomplications (5). Clinical and echocardiographicfollow-up was performed at discharge and at 1 and

12 months after implantation. For the echocardio-graphic analysis substudy, we selected centers(15 of 25) with a follow-up rate of at least 90% (n¼ 383),because we expected positive or negative bias tomodify the characteristics of the patients assessed inthe remaining centers. Only patients with pairedechocardiographic observations during follow-upwere included in the analysis (n ¼ 368 [61%]).

STATISTICAL ANALYSIS. Continuous variables arereported as mean � SD or as median and interquartilerange, as appropriate. Between-group comparisonswere made with a nonparametric test (Kruskal-Wallistest). Categorical variables are reported as percent-ages. Between-group comparisons were made with achi-square test (Fisher exact test if the expected cellcount was <5). Univariate analysis was applied toboth continuous and categorical variables. Multivar-iate logistic regression analysis was used to identifythe variables independently associated with thecombined endpoint of death or readmission becauseof heart failure at 1 year. We included all variablescorrelated with the combined endpoint at p < 0.1 orexpected from previous studies to influence outcome.Because we used the EuroSCORE (European Systemfor Cardiac Operative Risk Evaluation) as an overall

TABLE 1 Baseline Clinical Characteristics

Overall(n ¼ 628)

Mixed/Other

(n ¼ 17)Functional MR

(n ¼ 452)Degenerative MR

(n ¼ 143) p Value*

Age, yrs 74.2 � 9.7 78.0 � 8.4 72.8 � 9.8 78.3 � 8.5 <0.001

Male 63.1 41.2 67.7 52.5 <0.001

Diabetes mellitus 27.9 11.8 33.1 12.6 <0.001

Hypertension 75.9 88.2 77.6 69.0 0.038

COPD 19.3 11.8 19.8 20.3 0.905

Previous stroke 14.4 17.7 12.8 18.2 0.109

Significant CAD 30.9 29.4 31.9 25.9 0.659

Previous MI 31.2 25.5 37.6 13.3 <0.001

Previous PCI† 15.5 11.8 16.4 14.1 0.515

Previous CABG 32.3 35.3 34.9 21.7 <0.003

Previous valvesurgery

10.4 5.9 9.7 11.9 0.459

NYHA functionalclass

0.004

I 1.6 0.0 1.1 3.5

II 12.9 23.5 10.4 19.6

III 68.7 52.9 70.3 63.6

IV 16.8 23.5 18.2 13.3

AFib/flutter 31.7 18.8 27.2 50.0 <0.001

LVEF <30% 32.8 12.5 42.0 2.8 <0.001

Baseline SCr,mmol/l

132.0 � 80.5 115.7 � 37.2 137.7 � 88.0 112.6 � 45.8 0.002

CKD 30.5 17.7 32.8 24.1 0.051

Hemodialysis 9.2 0.0 9.3 10.5 0.634

EuroSCORE 20.4 � 16.7 15.5 � 11.2 21.9 � 17.6 16.3 � 13.7 0.003

Values are mean � SD or %. *p Value for comparisons between functional and degenerative mitral regurgitation.†Within 3 months.

AFib ¼ atrial fibrillation; CABG ¼ coronary artery bypass graft surgery; CAD ¼ coronary artery disease; CKD ¼chronic kidney disease; COPD ¼ chronic obstructive pulmonary disease; EuroSCORE ¼ European System forCardiac Operative Risk Evaluation; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; MR ¼mitral regurgitation; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; SCr ¼serum creatinine.

UK

Switzerland

Sweden

Italy

Germany

Denmark

Belgium

17.137.5

59.2

14.744.4

16.981.6

23.576.1

18.972.1

28.696.2

EuroSCORE

Functional MR (%)

FIGURE 2 Geographic Variation of Mean Logistic EuroSCORE

and Prevalence of Functional MR Pathogenesis

There is marked variation between countries with regard to

the type of mitral regurgitation (MR) treated and the surgical

predicted risk. EuroSCORE ¼ European System for Cardiac

Operative Risk Evaluation.

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878

estimation for the risk of patients, we excluded all thecomponents used for its calculation to avoid collin-earity. MR severity and New York Heart Association(NYHA) functional class were compared betweendifferent time points (baseline, discharge, 1 month,and 12 months) by use of the Bowker test. Changes inechocardiographic measurements between differenttime points (baseline, discharge, and 12 months) wereanalyzed with paired Student t tests. Survival ratesup to 12 months were presented as Kaplan-Meiercurves. Differences were considered statistically sig-nificant at p values <0.05.

All analyses were performed with SAS statisticalsoftware version 9.2 (SAS Institute, Inc., Cary, NorthCarolina). The multivariate logistic regression anal-ysis was performed with program R (Vienna Univer-sity of Economics and Business Administration,Vienna, Austria) and the package Hmisc (VanderbiltUniversity, Nashville, Tennessee).

RESULTS

BASELINE CHARACTERISTICS. Between January2011 and December 2012, 628 patients (mean age74.2 � 9.7 years) were entered into the database.Baseline characteristics for the entire population aredisplayed in Table 1. The prevalent pathogenesis wasfunctional mitral regurgitation (FMR) (n ¼ 452[72.0%]). In the overall population, men predomi-nated (63.1%), but patients with degenerative MR(DMR) showed an almost equal distribution of menand women (52% vs. 48%). The vast majority of pa-tients were highly symptomatic (NYHA functionalclass >III, 85.5%) and at high surgical risk (logisticEuroSCORE 20.4 � 16.7%). Mean logistic EuroSCOREand prevalence of FMR according to country are dis-played in Figure 2. There was a marked heterogeneityamong countries with regard to the pathogenesis ofMR and the surgical risk of patients selected forTMVR.

PROCEDURAL AND IN-HOSPITALOUTCOMES. Proceduralvariables and in-hospital outcomes are displayed inTable 2. Acute procedural success was high (95.4%)and equivalent between groups (p ¼ 0.304). One clipwas implanted in the majority of cases (61.4%), 2 clipswere implanted in 35.1% of cases, and very fewpatients received 3 or more clips (2.4%). Patients withDMR tended to receive a greater number of clips thanthose with FMR ($2 clips implanted in 62 patientswith DMR [44.3%] vs. 162 patients with FMR [36.5%],p ¼ 0.098). Overall, in-hospital mortality was 2.9%

TABLE 2 Procedural/In-Hospital Clinical Outcomes

Overall*(n ¼ 628)

FunctionalMR (n ¼ 452)

DegenerativeMR (n ¼ 143) p Value†

Death 2.9 2.0 4.9 0.075

Tamponade 1.1 0.7 1.8 0.298

Stroke 0.2 0.0 0.7 0.241

Severe bleeding 1.1 0.9 2.1 0.368

Transfusion 10.1 9.7 12.4 0.406

Vascular complicationrequiring intervention

0.7 1.0 0.0 0.581

New-onset atrialfibrillation

11.7 12.6 10.2 0.599

Acute proceduralsuccess

95.4 95.8 93.7 0.304

Clip embolization 0.7 0.5 0.9 0.521

Inability to reduceMR

3.5 3.0 4.4 0.387

Implant $2 clips 37.5 36.5 44.3 0.098

Procedure duration, min 138.3 � 67.9 137.2 � 68.2 132.1 � 65.6 0.463

Median hospitalstay (IQR), d

5 (3–7) 5 (4–7) 5 (3–7) 0.348

Values are % or mean � SD, unless otherwise noted. *Includes the 17 mixed/other patients.†p Value for comparisons between functional and degenerative mitral regurgitation.

IQR ¼ interquartile range; MR ¼ mitral regurgitation.

J A C C V O L . 6 4 , N O . 9 , 2 0 1 4 Nickenig et al.S E P T E M B E R 2 , 2 0 1 4 : 8 7 5 – 8 4 Percutaneous Mitral Valve Repair

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(18 of 628 patients) and ranged between 4.9% (7 of143 patients) in the DMR group and 2.0% (9 of452 patients) in the FMR group (p ¼ 0.075).Two patients died in the group with mixed/unknownpathogenesis. Cardiac tamponade and stroke wereinfrequent (1.1% and 0.2%, respectively). Vasculardamage and profuse bleeding that required multipletransfusions were rare (1.1% and 0.7%, respectively).The need for transfusion of at least 1 U of blood wasseen in 10.1% of patients.

ECHOCARDIOGRAPHIC DATA AT ADMISSION AND

DISCHARGE. Baseline and post-procedural pairedechocardiographic data are displayed in Table 3. Atbaseline, patients with FMR had larger LV volumes(p < 0.001) and a significantly lower LV ejectionfraction (LVEF; p < 0.001). By contrast, patients withDMR presented with more severe MR on both semi-quantitative and quantitative echocardiographic pa-rameters. They also had significantly higher systolicpulmonary pressure values (p < 0.001). Echocardio-grams obtained before discharge showed a markedreduction in MR less than or equal to moderate in98.2% of patients, with equivalence between groups(p ¼ 0.910). Overall, a significant reduction in atrialvolumes (mean change in left atrial volume 10.4 ml,p ¼ 0.004) and systolic pulmonary artery pressure(SPAP) (mean DSPAP 5.8 mm Hg, p < 0.001) wasobserved at discharge. LVEF showed a small but sig-nificant decrease after repair (mean DLVEF 1.0%,p ¼ 0.020), especially in the DMR group (DLVEF 4.4%,p < 0.001). In both FMR and DMR patients, significant

TABLE 3 Echocardiographic Variables Before and After TMVR

Overall (n ¼ 368)

Pre-Clip Post-Clip D p Value

LVEDV, ml 159.4 � 86.1 154.8 � 86.3 4.6 0.119

LVESV, ml 103.0 � 69.0 102.4 � 74.6 0.6 0.797 1

LA volume, ml 120.8 � 66.3 110.4 � 58.1 10.4 0.004 1

LVEF, % 42.6 � 15.9 41.6 � 15.0 1.0 0.020

Degree ofMR, %

<0.001

None/mild 0.7 72.8

Moderate 13.2 25.4

Severe 86.1 1.8

MR quantification

EROA, cm2 0.43 � 0.16 — —

VC, mm 7.5 � 2.7 — —

RV, ml 53.8 � 27.6 — —

Mean TMG, mm Hg 2.0 � 1.2 3.4 � 2.0 �1.4 <0.001

SPAP, mm Hg 46.0 � 14.5 40.2 � 11.7 5.8 <0.001

Values are mean � SD or %.

DMR ¼ degenerative mitral regurgitation; EROA ¼ effective regurgitant orifice area; Fventricular ejection fraction; LVESV ¼ left ventricular end-systolic volume; MR ¼ mitragradient; TMVR ¼ transcatheter mitral valve repair; VC ¼ vena contracta.

changes were demonstrated in atrial volume andpulmonary pressure. There was a significant increasein the mean transmitral pressure gradient for bothtypes of MR, but without significant differencesbetween groups.

FOLLOW-UP RESULTS: CLINICAL OUTCOMES. Twelve-month clinical follow-up was obtained in 552 patients

FMR (n ¼ 264) DMR (n ¼ 85)

Pre-Clip Post-Clip D p Value Pre-Clip Post-Clip D p Value

171.1 � 90.2 167.0 � 90.8 4.1 0.212 118.9 � 57.9 113.1 � 54.3 5.8 0.265

16.3 � 71.3 114.8 � 78.4 1.5 0.634 54.0 � 32.4 56.5 � 33.4 �2.5 0.313

22.5 � 59.7 113.4 � 57.9 9.1 0.029 114.1 � 85.4 99.3 � 63.2 14.8 0.040

37.1 � 13.6 37.0 � 13.5 0.1 0.792 59.9 � 9.3 55.5 � 9.6 4.4 <0.001

<0.001 <0.001

1.0 71.9 0 72.1

14.3 26.1 9.8 26.2

84.7 2.0 90.2 1.6

0.42 � 0.15 — — 0.46 � 0.18 — —

7.5 � 2.7 — — 7.6 � 2.9 — —

51.1 � 27.7 — — 62.7 � 21.3 — —

1.9 � 1.3 3.4 � 2.1 �1.5 <0.001 2.3 � 1.3 3.6 � 1.6 �1.3 0.003

44.2 � 13.2 39.2 � 11.2 5 <0.001 53.5 � 16.9 43.4 � 12.2 10.2 0.001

MR ¼ functional mitral regurgitation; LA ¼ left atrial; LVEDV ¼ left ventricular end-diastolic volume; LVEF ¼ leftl regurgitation; RV ¼ regurgitant volume; SPAP ¼ systolic pulmonary artery pressure; TMG ¼ transmitral pressure

Time, days

40

20

80

60

100

0

0 180 365

Surv

ival

, %

Log-Rank: p=0.103

Overall event-free survival rate:• 1-month=96.5%• 1-year=69%

Time, days

40

20

80

60

100

0

0 180 365

Surv

ival

, %

Log-Rank: p=0.009

Overall event-free survival rate:• 1-month=99%• 1-year=77.2%

Time, days

40

20

80

60

100

0

0 180 365

Surv

ival

, %

Log-Rank: p=0.650

Overall event-free survival rate:• 1-month=97%• 1-year=84.7%

+ censoreddegenerativefunctional

+ censoreddegenerativefunctional

+ censoreddegenerativefunctional

N at risk:Degenerative Functional

º

141441

103312

41116

N at risk:Degenerative Functional

º

141441

103312

41116

N at risk:Degenerative Functional

º

141443

106346

41138

A

B

C

CENTRAL ILLUSTRATION Kaplan-Meier Analysis of Survival Free From Death,

Rehospitalization Due to Heart Failure, and Composite of Death and Rehospitali-

zation, Comparing Degenerative Versus Functional Mitral Regurgitation

(A) Death, (B) rehospitalization due to heart failure, (C) composite of death and reho-

spitalization. We observed a significant difference between the 2 types of mitral regur-

gitation with regard to readmission because of heart failure; however, no differences

between groups with regard to death or the composite endpoint were noted.

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(88.0%). Median follow-up duration was 346 days(interquartile range: 211–385 days). The estimated1-year mortality was 15.3%, without significant dif-ferences between groups (FMR 15.0% vs. DMR 16.2%,p[log-rank] ¼ 0.650) (Central Illustration A). Theoverall Kaplan-Meier probability of survival at 1 yearwas 84.7% (SD 1.7%). The estimated 1-year rate ofrehospitalization because of heart failure was 22.8%and was significantly higher in the FMR group thanthe DMR group (25.8% vs. 12%, p[log-rank] ¼ 0.009)(Central Illustration B). Conversely, the probability ofbeing free from readmission was 77.2% (SD 2.2%).

At 1 year, the estimated rate of survival free fromdeath or readmission because of heart failure was69.0% (SD 2.3%). The Central Illustration C comparesthe survival curves of FMR and DMR in terms of deathand the composite endpoint of death plus rehospi-talization (p[log rank] ¼ 0.103).

The prevalence of different NYHA functional clas-ses during follow-up is shown in Figure 3. At 1 month,both FMR and DMR patients exhibited an improve-ment, with 74.9% (203 of 271 patients) of the formerand 76.5% (52 of 68 patients) of the latter showingimprovement. This effect persisted over 1 year, withmost patients in NYHA functional class II or lower.

Multivariate analysis showed that EuroSCORE(odds ratio [OR]: 1.44; 95% confidence interval [CI]:1.11 to 1.86; p ¼ 0.006), LVEF <30% (OR: 2.69; 95% CI:1.64 to 4.42; p < 0.001), and successful clip deploy-ment (OR: 0.12; 95% CI: 0.03 to 0.53; p ¼ 0.005) wereindependently associated with the compositeendpoint at 1 year.

Reintervention at 1 year was observed in 17patients (3.8%) in the overall population, consistingof an additional MitraClip implantation in 13 patients(2.9% of cases), surgical MV repair in 3 (0.7%), andMV replacement in 1 (0.2%). No significant differ-ences were observed between groups in terms ofreintervention.

ECHOCARDIOGRAPHIC FOLLOW-UP. MR reductionat hospital discharge and 1 year is shown in Figure 4. Atdischarge, no significant differences were observedbetween groups, with lower degrees of MR observed inthe FMR group. At 1 year, the rate of recurrence of se-vere MR in the DMR group was higher, albeit notsignificantly (6.6% vs. 5.9%, p ¼ 0.965).

At 1 year (Figure 5), we observed a slight, nonsig-nificant reduction in LV end-diastolic volume in pa-tients with DMR but no change in the FMR group. Theoverall cohort, especially DMR patients, showed adecrease in LVEF (D1.4% at 1 year compared with pre-clip, p ¼ 0.033). Patients with FMR experienced anonsignificant trend to an improvement in LVEF. Left

16.31.7

19.1

50.4

28.9

67.8

13.7

2.2

4.8

21.0

47.3

26.9

15.9

68.6

13.71.9

1.9 5.9

23.3

46.5

24.4

17.7

66.2

11.8

4.4

19.6

50.6

28.0

16.2

48.5

35.3

1.514.7

47.1

36.8

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

100

80

60

40

20

0% Baseline 1-Month

FU1-Year

FUBaseline 1-Month

FU1-Year

FUBaseline 1-Month

FU1-Year

FU

NHYA I NHYA II NHYA III NHYA IV

Overall (357) Functional (271) Degenerative (68)

FIGURE 3 NYHA Functional Class at Baseline and at 1-Month and 1-Year Follow-Up

We observed a relevant improvement in New York Heart Association (NYHA) functional

class in the overall cohort and for both types of mitral regurgitation (MR). At 1 year,

patients with functional MR were more frequently in NYHA functional class III or IV than

patients with degenerative MR. FU ¼ follow-up.

1.8

25.4

72.8

86.1

13.20.7

6.0

35.4

58.6

84.7

14.31.0

2.0 5.9

35.0

59.1

90.2

9.8

26.1

71.9

1.6

26.2

72.2

6.6

36.1

57.4

P<0.001

P<0.001

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P<0.001

P<0.001

P<0.001

100%

90%

80%

60%

40%

20%

0%

10%

30%

50%

70%

Baseline Discharge Discharge Discharge

Overall (368)

1-YearFU

Baseline

Functional (264)

1-YearFU

Baseline

Degenerative (85)

1-YearFU

SEVEREMODERATENO/MILD

FIGURE 4 Severity of Mitral Regurgitation at Baseline and Follow-Up (Discharge and

1-Year Follow-Up) After TMVR

A significant reduction in the degree of mitral regurgitation was noted, with no difference

between functional and degenerative mitral regurgitation. This reduction persisted at

1 year. FU ¼ follow-up; TMVR ¼ transcatheter mitral valve repair.

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atrial volumes decreased significantly, mainly in theFMR group. SPAP showed a persistent significantdecrease at 1 year (D5.2 mm Hg, p < 0.001). Finally,the significant increase in mean transmitral pressuregradient that appeared during the in-hospital evalu-ation was persistent at 1 year (Figure 6).

DISCUSSION

This first report from the mitral cohort of the TCVTEuropean Sentinel registry presents one of thelargest independent, contemporary, real-world datacollections on the safety and efficacy of MV repairwith percutaneous TMVR. Acute procedural successwas greater (>90%) than in the initial randomizedEVEREST trial but similar to the success observed inmore recent registries (10–15,19,20).

This registry also confirms that patients enrolledin contemporary clinical practice are very differentfrom the patients enrolled in the EVEREST clinicaltrial, which was limited to surgical candidates, mainlywith preserved LV function and degenerative valvedisease. With regard to the cause of MR, 72% wasfunctional, at variance with EVEREST II (27% preva-lence of FMR) but similar to recent registries (66% inTRAMI [Transcatheter Mitral Valve Interventions],69% in ACCESS-EU [ACCESS-Europe, A Two-PhaseObservational Study of the MitraClip System inEurope], and 60% in EVEREST high-risk) (11,13,21). Inthe present registry, there was a high prevalenceof ischemic heart disease, LV dysfunction, andNYHA functional class III or IV (>85% of patients).These features, together with other comorbidities andthe old age of the patients, especially in the DMRgroup, translated into a high logistic EuroSCORE,with an average >20%. The widespread use of TMVRfor patients with heart failure and secondary MR isexplained by the suboptimal results and high mor-tality of surgical correction (22–24). In EVEREST II,patients with advanced age, secondary FMR, anddepressed LVEF had similar results with TMVR andsurgery, compared with previous registries focusedon this high-risk group that showed promising re-sults for both MR reduction and functional classimprovement (7–9,11,13,21,25).

It is important to stress the overall high acuteprocedural success (95.4%) achieved with a techni-cally demanding procedure, which was similarbetween the FMR and DMR groups. Notably, acuteprocedural success was even higher than in contem-porary registries (91% in ACCESS-EU and 94% inTRAMI) (13,21). Greater operator, imaging, and anes-thesiology team experience is the most likely expla-nation for the greater MR reduction with fewer

complications and a shorter procedure time than inearly reports (26). It is important to highlight thatalmost 38% of patients received more than 1 clip, andnearly half of the patients with DMR required $2

200

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ml

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157.7

P=0.119

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P=0.183 P=0.004

P=0.001

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P=0.745

P=0.634

P=0.578P=0.029

P=0.0001

P=0.265

P=0.196

P=0.313

P=0.249

P=0.040

P=0.730

103102.4

107

120.8110.4

105.6

171.1 172.5167

116.3 118114.8

122.5113.4

103.9

118.9113.1

108.3

54 56.560.8

114.199.3

109.4

LVEDV LVESV LA LVEDV LVESV LA LVEDV LVESV LAOverall Functional Degenerative

Baseline Discharge 1-Year FU

FIGURE 5 Echocardiographic Measurement of Left Ventricular and

Left Atrial Volumes at Baseline, Discharge, and 1-Year Follow-Up After TMVR

(Paired Data From 368 Patients)

In the overall cohort, a nonsignificant reduction in left ventricular end-diastolic volume

(LVEDV) was observed, with a significant reduction in left atrial volume (LA). In functional

mitral regurgitation, left ventricular volumes remained stable during follow-up, although a

significant reduction in LA was noted. In degenerative mitral regurgitation, the most

relevant finding was a reduction in LVEDV over time (nonsignificant). LVESV ¼ left ven-

tricular end-systolic volume; TMVR ¼ transcatheter mitral valve repair.

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clips. The EVEREST subanalysis (27) showed thatpatients with more severe MR (measured by higherregurgitant volumes) were more likely to receivemore than 1 clip to achieve an optimal MR reduction,

Overall Functional Degenerative

60

50

40

30

20

10

0mmHg

TMG SPAP TMG SPAP TMG SP

53.5

40.539.2

44.246.0 40.8

40.2

1.9 3.4 3.5 2.3 3.6 4.52 3.4 3.7

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P=0.003

P=0.005

P<0.001

P<

P=0.0

Baseline Discha

FIGURE 6 Echocardiographic Measurement of Transmitral Pressure

and 1-Year Follow-Up

Significant and persistent reductions in systolic pulmonary artery pressu

transmitral pressure gradient (TMG) (mm Hg) increased significantly, alt

ventricular ejection fraction (%).

whereas previous data from Franzen et al. (8) showedthat in 80% of patients with end-stage heart failure,MR can be successfully treated with a single clip.Successful reduction of MR is of paramount impor-tance to maximize the clinical benefit of the proce-dure (19,28). With proper patient selection, theimplantation of $2 clips is not associated with highergradients or lower MV area at follow-up than the useof just 1 clip (29).

Numerically, in-hospital mortality was lower thanin previous registries in high-risk populations(10,11,13,19), with higher rates observed in the DMRthan in the FMR group. This finding may be explainedby the fact that although patients with DMR hadlower logistic EuroSCOREs and therefore expectedlower rates of in-hospital adverse events, they weresignificantly older and had more severe MR and pul-monary hypertension, together with other adversefactors that were not taken into account in the riskscore calculation.

The registry confirmed that TMVR confers sus-tained clinical benefit, with persistent severe MR in1.8% of cases immediately post-procedure and 6% at 1year, a long-term improvement already observed inother real-world registries (e.g., 80% MR #2þ inACCESS-EU at 1 year) (12,13,21). Patients with DMR, inwhom regurgitant volume plays the key role in thepathophysiology of LV remodeling, showed aconsiderable although not significant decrease in LVend-diastolic volume. Conversely, in patients withFMR, LV volumes at 1 year presented an increase fromthe post-procedure values, likely caused by the

Overall Functional Degenerative

60

50

40

30

20

10

0AP LVEF

52.455.5

59.9

37.837.0

37.141.241.6

42.642.9

43.4

0.001

01

P=0.033

P=0.02 P=0.294

P=0.792

P<0.001

P<0.001

rge 1-Year FU

%

Gradient, SPAP, and Ejection Fraction, at Baseline, Discharge,

re (SPAP) were observed. After transcatheter mitral valve repair,

hough no cases of severe mitral stenosis were reported. LVEF ¼ left

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Experience in

Europe with percutaneous TMVR suggests efficacy in reducing

the severity of primary mitral regurgitation with a relatively low

complication rate and persistent improvement in functional class

in most patients.

TRANSLATIONAL OUTLOOK: The results of randomized

trials should provide more information about the value of TMVR

as a palliative adjunctive treatment of heart failure patients with

severe primary mitral regurgitation refractory to mediation

therapy.

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underlying myocardial disease. The correction ofmitral insufficiency alters just 1 of the multiplemechanisms that lead to progressive LV dilation, andLV volumes can remain high despite a significantreverse atrial remodeling after implantation of theclip, a finding that suggests an effective correctionof the volume overload. It must be stressed as wellthat patients with FMR in this trial were treated inan advanced stage of evolution of their disease.With earlier correction of MR, we speculate that afavorable LV remodeling may still occur. Volumetricreductions were more pronounced in the EVERESTtrial, which is possibly explained by the inclusionof an older population with more advanced diseasein our registry. In addition, the different proportionof patients with DMR and FMR may account forthe differences observed between our data and theEVEREST analyses with regard to LV remodeling(30,31).

NYHA functional class showed improvement dur-ing follow-up for both FMR and DMR patients,although at 1 year, the proportion of patients withFMR in a more advanced functional class was higherthan in patients with DMR. The 1-year mortality ratewas comparable to the mortality reported in the mostrecent registry (21), with no significant difference inthe rate of mortality of FMR and DMR patients. Thevariable with the strongest association with thecombined endpoint of death or rehospitalization forheart failure was the inability to implant a clip andreduce MR. This finding was addressed recently in areport from the EVEREST investigators in a subset ofpatients with DMR: The degree of residual MR afterthe procedure was linked to a worse outcome, with anincrease in the rates of death and rehospitalizationbecause of heart failure (32). Notably, our data andthe recently published ACCESS-EU (21) show a 1-yearsurvival that is similar to the rate in the mostcontemporary trial of surgical correction of FMR butin patients with very high surgical risk (33).

STUDY LIMITATIONS. First, the TCVT registry is apilot, voluntary registry. Thus, procedural complica-tions, adverse events, and echocardiography param-eters are self-reported. Second, despite the extremesimplification of the follow-up data requested, whichexcluded, for instance, drug regimen, the complete-ness of follow-up for clinical events (88%) andespecially echocardiographic data (61%) is far fromideal. However, the centers compliant with fullechocardiographic data entry provided nearly com-plete entry of their consecutive 368 patients withpaired echocardiographic data, a group that is one ofthe largest series in the literature and reports

complete data in terms of serial volumes and atrio-ventricular gradients, which are essential to under-stand the effects of TMVR on LV remodeling and MRreduction.

Registries do not eliminate the need for properlyrandomized controlled trials with external adjudica-tion and core laboratory analysis of data with greatsubjectivity, such as, for instance, severity of mitralinsufficiency. Still, they offer the opportunity to un-derstand whether trial results are applicable to real-life settings and, conversely, help to provide the keyoutcome measures to design meaningful futurecontrolled studies.

CONCLUSIONS

In this large contemporary registry addressing theeffect of TMVR on MR reduction, functional classimprovement, and clinical events, both FMR andDMR exhibited an immediate reduction in theseverity of MR and improvement in functional classthat persisted at 1 year. Procedural and late mortalitywas low and lower than expected in such a high-riskcohort, without differences between FMR and DMR.

ACKNOWLEDGEMENTS The authors gratefully ac-knowledge that the statistical analysis was indepen-dently performed by Cécile Laroche, PhD, from theEuropean Heart House, with review of results andsupport to the multivariate analysis offered by AldoMaggioni, Scientific Coordinator of EORP, and RenatoUrso, European Heart House. The authors alsoacknowledge the careful review of Michael Schluter,PhD.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Carlo Di Mario, National Institute of Health Research,Cardiovascular Biomedical Research Unit, RoyalBrompton Hospital, Sydney Street, SW3 6NP London,United Kingdom. E-mail: [email protected].

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KEY WORDS MitraClip, mitralregurgitation, percutaneous mitral valverepair, registry

APPENDIX For supplemental material,please see the online version of this article.